Congenital adrenal hyperplasia encompasses several autosomal recessive disorders with complete or partial deficiency of an enzyme involved in the cortisol or aldosterone synthesis.
Adrenal Virilism; Congenital Adrenal Hyperplasia (CAH). Included: Lipoid Adrenal Hyperplasia (20,22-Desmolase Deficiency; Cholesterol Desmolase Complex Defect)
Worldwide, the frequency of the classic form is estimated to be 1 in 5,000 to 15,000. However, in the Yupik indigenous people of Alaska, the disease occurs in up to 1 in 282 neonates.
Most often autosomal recessive inheritance. Spontaneous mutations are possible.
The common finding in all of these cases is an elevated adrenocorticotropic hormone (ACTH) level resulting from significantly decreased negative feedback of cortisol on ACTH secretion in the pituitary gland. Congenital adrenal hyperplasia (CAH) with the histopathologic finding of adrenal cortical hyperplasia is the result of these elevated ACTH levels. Any of the steps involved in adrenal steroid synthesis can be affected (see Table A-1). The classic form, which is responsible for approximately 90% of all cases of CAH, is characterized by absent or decreased activity of the enzyme 21-hydroxylase. The classic form refers to early-diagnosed 21-hydroxylase deficiency, while the non-classic form with the same enzyme defect describes the late-diagnosed disorder (due to absence of salt wasting and developmental abnormalities) with signs of hyperandrogenism. Approximately 5 to 8% of CAH cases are caused by a dysfunction of the enzyme 11-β-hydroxylase. In the remainder of patients with CAH, the enzyme defect affects either 17α-hydroxylase or 3β-hydroxysteroid dehydrogenase. Depending on the enzyme defect, the symptoms can vary widely. Classical forms with all the typical symptoms are often distinguished from non-classical forms presenting with a generally milder course and often delayed onset.
TABLE A-1Adrenal Steroid Biosynthesis
Deficiency of StAR (steroidogenic acute regulatory) protein causes lipoid adrenal hyperplasia (Synonyms: 20,22-Desmolase Deficiency; Cholesterol Desmolase Complex Defect) and is the most severe form of CAH as it blocks the first step in adrenal and gonadal steroidogenesis and thus affects all adrenal and gonadal hormones. It is most often due to mutations in the StAR-gene encoding StAR protein, which is essential for the transport of cytosolic cholesterol across the mitochondrial membrane into the mitochondrium, where cholesterol side-chain cleavage by cytochrome P450 (P-450scc or formerly known as 20,22-cholesterol desmolase) converts it to pregnenolone. The StAR gene has been mapped to chromosome 8p11.23. A deficiency in P-450scc can also result in lipoid adrenal hyperplasia, which gets its name from the marked nodular enlargement of the adrenal cortex secondary to accumulation of large cytoplasmic lipoid droplets. The affected cells are called spongiocytes and the lipoid droplets consist of cholesterol. Because of the profound lack of steroids, symptoms ...